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Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response

The current pathological and molecular classification of pancreatic ductal adenocarcinoma (PDAC) provides limited guidance for treatment options, especially for immunotherapy. Cancer-associated fibroblasts (CAFs) are major players of desmoplastic stroma in PDAC, modulating tumor progression and ther...

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Autores principales: Wang, Yu, Liang, Yiyi, Xu, Haiyan, Zhang, Xiao, Mao, Tiebo, Cui, Jiujie, Yao, Jiayu, Wang, Yongchao, Jiao, Feng, Xiao, Xiuying, Hu, Jiong, Xia, Qing, Zhang, Xiaofei, Wang, Xujun, Sun, Yongwei, Fu, Deliang, Shen, Lei, Xu, Xiaojiang, Xue, Jing, Wang, Liwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Singapore 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149399/
https://www.ncbi.nlm.nih.gov/pubmed/34035226
http://dx.doi.org/10.1038/s41421-021-00271-4
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author Wang, Yu
Liang, Yiyi
Xu, Haiyan
Zhang, Xiao
Mao, Tiebo
Cui, Jiujie
Yao, Jiayu
Wang, Yongchao
Jiao, Feng
Xiao, Xiuying
Hu, Jiong
Xia, Qing
Zhang, Xiaofei
Wang, Xujun
Sun, Yongwei
Fu, Deliang
Shen, Lei
Xu, Xiaojiang
Xue, Jing
Wang, Liwei
author_facet Wang, Yu
Liang, Yiyi
Xu, Haiyan
Zhang, Xiao
Mao, Tiebo
Cui, Jiujie
Yao, Jiayu
Wang, Yongchao
Jiao, Feng
Xiao, Xiuying
Hu, Jiong
Xia, Qing
Zhang, Xiaofei
Wang, Xujun
Sun, Yongwei
Fu, Deliang
Shen, Lei
Xu, Xiaojiang
Xue, Jing
Wang, Liwei
author_sort Wang, Yu
collection PubMed
description The current pathological and molecular classification of pancreatic ductal adenocarcinoma (PDAC) provides limited guidance for treatment options, especially for immunotherapy. Cancer-associated fibroblasts (CAFs) are major players of desmoplastic stroma in PDAC, modulating tumor progression and therapeutic response. Using single-cell RNA sequencing, we explored the intertumoral heterogeneity among PDAC patients with different degrees of desmoplasia. We found substantial intertumoral heterogeneity in CAFs, ductal cancer cells, and immune cells between the extremely dense and loose types of PDACs (dense-type, high desmoplasia; loose-type, low desmoplasia). Notably, no difference in CAF abundance was detected, but a novel subtype of CAFs with a highly activated metabolic state (meCAFs) was found in loose-type PDAC compared to dense-type PDAC. MeCAFs had highly active glycolysis, whereas the corresponding cancer cells used oxidative phosphorylation as a major metabolic mode rather than glycolysis. We found that the proportion and activity of immune cells were much higher in loose-type PDAC than in dense-type PDAC. Then, the clinical significance of the CAF subtypes was further validated in our PDAC cohort and a public database. PDAC patients with abundant meCAFs had a higher risk of metastasis and a poor prognosis but showed a dramatically better response to immunotherapy (64.71% objective response rate, one complete response). We characterized the intertumoral heterogeneity of cellular components, immune activity, and metabolic status between dense- and loose-type PDACs and identified meCAFs as a novel CAF subtype critical for PDAC progression and the susceptibility to immunotherapy.
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spelling pubmed-81493992021-05-27 Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response Wang, Yu Liang, Yiyi Xu, Haiyan Zhang, Xiao Mao, Tiebo Cui, Jiujie Yao, Jiayu Wang, Yongchao Jiao, Feng Xiao, Xiuying Hu, Jiong Xia, Qing Zhang, Xiaofei Wang, Xujun Sun, Yongwei Fu, Deliang Shen, Lei Xu, Xiaojiang Xue, Jing Wang, Liwei Cell Discov Article The current pathological and molecular classification of pancreatic ductal adenocarcinoma (PDAC) provides limited guidance for treatment options, especially for immunotherapy. Cancer-associated fibroblasts (CAFs) are major players of desmoplastic stroma in PDAC, modulating tumor progression and therapeutic response. Using single-cell RNA sequencing, we explored the intertumoral heterogeneity among PDAC patients with different degrees of desmoplasia. We found substantial intertumoral heterogeneity in CAFs, ductal cancer cells, and immune cells between the extremely dense and loose types of PDACs (dense-type, high desmoplasia; loose-type, low desmoplasia). Notably, no difference in CAF abundance was detected, but a novel subtype of CAFs with a highly activated metabolic state (meCAFs) was found in loose-type PDAC compared to dense-type PDAC. MeCAFs had highly active glycolysis, whereas the corresponding cancer cells used oxidative phosphorylation as a major metabolic mode rather than glycolysis. We found that the proportion and activity of immune cells were much higher in loose-type PDAC than in dense-type PDAC. Then, the clinical significance of the CAF subtypes was further validated in our PDAC cohort and a public database. PDAC patients with abundant meCAFs had a higher risk of metastasis and a poor prognosis but showed a dramatically better response to immunotherapy (64.71% objective response rate, one complete response). We characterized the intertumoral heterogeneity of cellular components, immune activity, and metabolic status between dense- and loose-type PDACs and identified meCAFs as a novel CAF subtype critical for PDAC progression and the susceptibility to immunotherapy. Springer Singapore 2021-05-25 /pmc/articles/PMC8149399/ /pubmed/34035226 http://dx.doi.org/10.1038/s41421-021-00271-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wang, Yu
Liang, Yiyi
Xu, Haiyan
Zhang, Xiao
Mao, Tiebo
Cui, Jiujie
Yao, Jiayu
Wang, Yongchao
Jiao, Feng
Xiao, Xiuying
Hu, Jiong
Xia, Qing
Zhang, Xiaofei
Wang, Xujun
Sun, Yongwei
Fu, Deliang
Shen, Lei
Xu, Xiaojiang
Xue, Jing
Wang, Liwei
Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response
title Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response
title_full Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response
title_fullStr Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response
title_full_unstemmed Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response
title_short Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response
title_sort single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149399/
https://www.ncbi.nlm.nih.gov/pubmed/34035226
http://dx.doi.org/10.1038/s41421-021-00271-4
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